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A more recent version of this article appeared on December 1, 2003
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Submitted on June 10, 2003
Revised on August 8, 2003
Accepted on August 18, 2003
1 Departments of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California, 92093
2 Departments of Cellular and Molecular Medicine and Pathology, University of California San Diego, La Jolla, California, 92093
* Corresponding author. E-mail address: mfarquhar{at}ucsd.edu.
Megalin is an endocytic receptor that binds multiple ligands and is essential for many physiological processes such as brain development and uptake of proteins by the kidney tubule, yolk sac, and thyroid. The cytoplasmic tail of megalin contains two FXNPXY motifs. ARH (autosomal recessive hypercholesterolemia) is an adaptor protein that binds to the FXNPXY motif of the LDL receptor as well as clathrin and AP-2. We found that ARH also binds to the first FXNPXY motif of megalin in two hybrid, pull-down and coimmunoprecipitation assays. ARH colocalizes with megalin in clathrin coated pits (CCPs) and in recycling endosomes in the Golgi region. When cells are treated with nocodazole, the recycling endosomes containing megalin and ARH disperse. On internalization of megalin, ARH and megalin are first seen in CCPs followed by sequential localization in early endosomes and tubular recycling endosomes in the pericentriolar region followed by their reappearance at the cell surface. Expression of ARH in MDCK cells expressing megalin minireceptors enhances megalin mediated uptake of 125I-lactoferrin, a megalin ligand. These results show that ARH facilitates endocytosis of megalin, escorts megalin along its endocytic route and raise the possibility that transport through the endosomal system is selective and requires interaction with specific adaptor proteins.
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